Substituted pyridazine carboxamide compounds as kinase inhibitor compounds

ABSTRACT

The new pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases especially against c-Met and are useful in treating disorders related to abnormal protein kinase activities such as cancer.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional application61/391,464, filed on Oct. 8, 2010, the contents of which areincorporated in its entirety.

TECHNICAL FIELD OF THE INVENTION

This invention relates to novel pyridazine derivatives, their salts,solvates, hydrates and polymorphs thereof. The invention also providescompositions comprising a compound of this invention and the use of suchcompositions in methods of treating diseases and conditions associatedwith protein kinase modulation.

BACKGROUND OF THE INVENTION

Protein kinases are enzymes that catalyze the phosphorylation ofhydroxyl groups of tyrosine, serine, and threonine residues of proteins.Many aspects of cell life (for example, cell growth, differentiation,proliferation, cell cycle and survival) depend on protein kinaseactivities. Furthermore, abnormal protein kinase activity has beenrelated to a host of disorders such as cancer and inflammation.Therefore, considerable effort has been directed to identifying ways tomodulate protein kinase activities. In particular, many attempts havebeen made to identify small molecules that act as protein kinaseinhibitors.

The c-Met proto-oncogene encodes the Met receptor tyrosine kinase. TheMet receptor is a 190 kDa glycosylated dimeric complex composed of a 50kDa alpha chain disulfide-linked to a 145 kDa beta chain. The alphachain is found extracellularly while the beta chain containstransmembrane and cytosolic domains. Met is synthesized as a precursorand is proteolytically cleaved to yield mature alpha and beta subunits.It displays structural similarities to semaphorins and plexins, aligand-receptor family that is involved in cell-cell interaction. Theligand for Met is hepatocyte growth factor (HGF), a member of thescatter factor family and has some homology to plasminogen (Longati, P.et al., Curr. Drug Targets 2001, 2, 41-55); Trusolino, L. and Comoglio,P. Nature Rev. Cancer 2002, 2, 289-300].

Met functions in tumorigenesis and tumor metastasis. Expression of Metalong with its ligand HGF is transforming, tumorigenic, and metastatic(Jeffers, M. et al., Oncogene 1996, 13, 853-856; Michieli, P. et al.,Oncogene 1999, 18, 5221-5231). MET is overexpressed in a significantpercentage of human cancers and is amplified during the transitionbetween primary tumors and metastasis. Numerous studies have correlatedthe expression of c-MET and/or HGF/SF with the state of diseaseprogression of different types of cancer (including lung, colon, breast,prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin, andbone cancers). Furthermore, the overexpression of c-MET or HGF have beenshown to correlate with poor prognosis and disease outcome in a numberof major human cancers including lung, liver, gastric, and breast. c-METhas also been directly implicated in cancers without a successfultreatment regimen such as pancreatic cancer, glioma, and hepatocellularcarcinoma.

Met mutants exhibiting enhanced kinase activity have been identified inboth hereditary and sporadic forms of papillary renal carcinoma(Schmidt, L. et al., Nat. Genet. 1997, 16, 68-73; Jeffers, M. et al.,Proc. Nat. Acad. Sci. 1997, 94, 11445-11500). HGF/Met has been shown toinhibit anoikis, suspension-induced programmed cell death (apoptosis),in head and neck squamous cell carcinoma cells. Anoikis resistance oranchorage-independent survival is a hallmark of oncogenic transformationof epithelial cells (Zeng, Q. et al., J. Biol. Chem. 2002, 277,25203-25208).

Increased expression of Met/HGF is seen in many metastatic tumorsincluding colon (Fazekas, K. et al., Clin. Exp. Metastasis 2000, 18,639-649), breast (Elliott, B. E. et al., 2002, Can. J. Physiol.Pharmacol. 80, 91-102), prostate (Knudsen, B. S. et al., Urology 2002,60, 1113-1117), lung (Siegfried, J. M. et al., Ann. Thorac. Surg. 1998,66, 1915-1918), and gastric (Amemiya, H. et al., Oncology 2002, 63,286-296). HGF-Met signaling has also been associated with increased riskof atherosclerosis (Yamamoto, Y. et al., J. Hypertens. 2001, 19,1975-1979; Morishita, R. et al., Endocr. J. 2002, 49, 273-284) andincreased fibrosis of the lung (Crestani, B. et al., Lab. Invest. 2002,82, 1015-1022).

2-amino-pyridines, such as PF-2341066, have been reported as potentinhibitors of the HGF receptor tyrosine kinase (c-Met) and ALK (J. G.Christensen, et al. Abstract LB-271, AACR 2006 meeting; H. Y. Zou et al.Cancer Res 2007; 67: 4408; patent disclosures: WO 2004076412, WO2006021881, WO 2006021886).

Previously, we described the substituted pyridazine carboxamidecompounds as protein kinase inhibitors (WO 2009/154769). Most of thesecompounds potently inhibit c-Met and ALK with IC50 of <100 nM. Thisinvention discloses the unsaturated heterocycle substituted pyridazinecarboxamide as more selective c-Met inhibitors.

SUMMARY OF THE INVENTION

The invention relates to pyridazine derivative compounds (e.g., any ofthe formulae herein), compositions comprising the compounds, and methodsof using the compounds and compound compositions. The compounds andcompositions comprising them are useful for treating or preventingdisease or disease symptoms, including those mediated by or associatedwith protein kinase modulation activity.

The present invention solves the problems set forth above by providingan isolated compound of Formula I

or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or ahydrate, solvate, or polymorph thereof; wherein:

R₁, R₂, R₃, and R₄ each are independently H, alkyl, or Z¹;

R₆ is an unsaturated heterocyclyl, wherein R₆ is optionally substitutedby 1-3 groups independently selected from alkyl, cycloalkyl,heterocyclyl, alkoxy, hydroxyalkyl, and Z¹;

Each Z¹ is halogen, CN, NO₂, OR¹⁵, SR¹⁵, S(O)₂OR¹, NR¹⁵R¹⁶, C₁-C₂perfluoroalkyl, C₁-C₂ perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR¹⁵,C(O)NR¹⁵R¹⁶OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶,NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶, R¹⁷, C(O)R¹⁷, NR¹⁵C(O)R¹⁷, S(O)R¹⁷,S(O)₂R¹⁷, R¹⁶, oxo, C(O)R¹⁶, C(O)(CH₂)nOH, (CH₂)nOR¹⁵,(CH₂)nC(O)NR¹⁵R¹⁶, NR¹⁵S(O)₂R¹⁷, where each n is independently 0-6;

Each R¹⁵ is independently hydrogen, C₁-C₄ alkyl or C₃-C₆ cycloalkyl;

Each R¹⁶ is independently hydrogen, alkenyl, alkynyl, C₃-C₆ cycloalkyl,aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substitutedwith C₃-C₆ cycloalkyl, aryl, heterocyclyl or heteroaryl; and

Each R¹⁷ is independently C₃-C₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substituted with C₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl.

The compounds of this invention, and compositions comprising them, areuseful for treating or lessening the severity of protein kinasemodulated diseases, disorders, or symptoms thereof, i.e., disorderseffectively treated by inhibitors of protein kinases, especially c-met.

In another aspect, the invention relates to a method of treating adisease or disease symptom in a subject in need thereof includingadministering to the subject an effective amount of a compound of anyformulae herein, or pharmaceutical salt, solvate or hydrate thereof (orcomposition thereof). The disease or disease symptom can be any of thosemodulated by a protein kinase (e.g. c-met). The disease or diseasesymptom can be, for example, cancer or proliferation disease or disorder(e.g., including those delineated herein).

DETAILED DESCRIPTION OF THE INVENTION Description of the Drawings

FIG. 1 showed c-Met expression in all these cell lines. U87MG, PC3 andCaki cells expressed phosphorylated high level of c-Met. Compared tototal c-Met expression level, U87-MG showed the most elevatedphospho-c-Met level and thus it was selected for in vivo studies.

FIG. 2. Growth inhibition of EXAMPLE 1 on U-87 MG xenograft tumor model.The data graph shows the tumor volume of U-87 MG in Balb/c nude mice.Lines, mean tumor volume for each group, bars, ±S.E.

DEFINITIONS

The terms “ameliorate” and “treat” are used interchangeably and bothmean decrease, suppress, attenuate, diminish, arrest, or stabilize thedevelopment or progression of a disease (e.g., a disease or disorderdelineated herein).

By “disease” is meant any condition or disorder that damages orinterferes with the normal function of a cell, tissue, or organ.

By “marker” is meant any alteration that is associated with a disease ordisorder.

For example, any protein or polynucleotide having an alteration inexpression level or activity that is associated with a disease ordisorder.

In this disclosure, “comprises,” “comprising,” “containing” and “having”and the like can have the meaning ascribed to them in U.S. patent lawand can mean “includes,” “including,” and the like; “consistingessentially of” or “consists essentially” likewise has the meaningascribed in U.S. patent law and the term is open-ended, allowing for thepresence of more than that which is recited so long as basic or novelcharacteristics of that which is recited is not changed by the presenceof more than that which is recited, but excludes prior art embodiments.

The term “compound” as used herein, is also intended to include salts,prodrugs, and prodrug salts of a compound of formulae herein. The termalso includes any solvates, hydrates, and polymorphs of any of theforegoing. The specific recitation of “prodrug,” “prodrug salt,”“solvate,” “hydrate,” or “polymorph” in certain aspects of the inventiondescribed in this application shall not be interpreted as an intendedomission of these forms in other aspects of the invention where the term“compound” is used without recitation of these other forms.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another preferred embodiment, the compound is apharmaceutically acceptable acid addition salt.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may only become active upon suchreaction under biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds ofany one of the formulae disclosed herein that comprise biohydrolyzablemoieties such as amides, esters, carbamates, carbonates, and phosphateanalogues. Prodrugs can typically be prepared using well-known methods,such as those described by Burger's Medicinal Chemistry and DrugDiscovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed); seealso Goodman and Gilman's, The Pharmacological basis of Therapeutics,8th ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”.

As used herein and unless otherwise indicated, the term “biohydrolyzablemoiety” means a functional group (e.g., amide, ester, carbamate,carbonate, or phosphate analogue, that either: 1) does not destroy thebiological activity of the compound and confers upon that compoundadvantageous properties in vivo, such as uptake, duration of action, oronset of action; or 2) is itself biologically inactive but is convertedin vivo to a biologically active compound.

A prodrug salt is a compound formed between an acid and a basic group ofthe prodrug, such as an amino functional group, or a base and an acidicgroup of the prodrug, such as a carboxyl functional group. In a oneembodiment, the prodrug salt is a pharmaceutically acceptable salt.

Particularly favored prodrugs and prodrug salts are those that increasethe bioavailability of the compounds of this invention when suchcompounds are administered to a mammal (e.g., by allowing an orallyadministered compound to be more readily absorbed into the blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or central nervous system) relative to theparent species. Preferred prodrugs include derivatives where a groupthat enhances aqueous solubility or active transport through the gutmembrane is appended to the structure of formulae described herein. See,e.g., Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31,318-322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp1-92; Bundgaard, H.; Nielsen, N. M. Journal of Medicinal Chemistry 1987,30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development;Harwood Academic Publ.: Switzerland, 1991; pp 113-191; Digenis, G. A. etal. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, G.J.; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.;Overseas Publ.: Amsterdam, 1996; pp 351-385; Pitman, I. H. MedicinalResearch Reviews 1981, 1, 189-214.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound or a prodrug of a compound of this invention.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric,hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well asorganic acids such as para-toluenesulfonic, salicylic, tartaric,bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic,formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic,lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric,benzoic and acetic acid, and related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephathalate, sulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the likesalts. Preferred pharmaceutically acceptable acid addition salts includethose formed with mineral acids such as hydrochloric acid andhydrobromic acid, and especially those formed with organic acids such asmaleic acid.

Suitable bases for forming pharmaceutically acceptable salts with acidicfunctional groups of prodrugs of this invention include, but are notlimited to, hydroxides of alkali metals such as sodium, potassium, andlithium; hydroxides of alkaline earth metal such as calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike.

As used herein, the term “hydrate” means a compound which furtherincludes a stoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein, the term “solvate” means a compound which furtherincludes a stoichiometric or non-stoichiometric amount of solvent suchas water, acetone, ethanol, methanol, dichloromethane, 2-propanol, orthe like, bound by non-covalent intermolecular forces.

As used herein, the term “polymorph” means solid crystalline forms of acompound or complex thereof which may be characterized by physical meanssuch as, for instance, X-ray powder diffraction patterns or infraredspectroscopy. Different polymorphs of the same compound can exhibitdifferent physical, chemical and/or spectroscopic properties. Differentphysical properties include, but are not limited to stability (e.g., toheat, light or moisture), compressibility and density (important informulation and product manufacturing), hygroscopicity, solubility, anddissolution rates (which can affect bioavailability). Differences instability can result from changes in chemical reactivity (e.g.,differential oxidation, such that a dosage form discolors more rapidlywhen comprised of one polymorph than when comprised of anotherpolymorph) or mechanical characteristics (e.g., tablets crumble onstorage as a kinetically favored polymorph converts to thermodynamicallymore stable polymorph) or both (e.g., tablets of one polymorph are moresusceptible to breakdown at high humidity). Different physicalproperties of polymorphs can affect their processing. For example, onepolymorph might be more likely to form solvates or might be moredifficult to filter or wash free of impurities than another due to, forexample, the shape or size distribution of particles of it.

The term “substantially free of other stereoisomers” as used hereinmeans less than 25% of other stereoisomers, preferably less than 10% ofother stereoisomers, more preferably less than 5% of other stereoisomersand most preferably less than 2% of other stereoisomers, or less than“X” % of other stereoisomers (wherein X is a number between 0 and 100,inclusive) are present. Methods of obtaining or synthesizingdiastereomers are well known in the art and may be applied aspracticable to final compounds or to starting material or intermediates.Other embodiments are those wherein the compound is an isolatedcompound. The term “at least X % enantiomerically enriched” as usedherein means that at least X % of the compound is a single enantiomericform, wherein X is a number between 0 and 100, inclusive.

The term “stable compounds”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintain theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., formulation into therapeuticproducts, intermediates for use in production of therapeutic compounds,isolatable or storable intermediate compounds, treating a disease orcondition responsive to therapeutic agents).

“Stereoisomer” refers to both enantiomers and diastereomers.

As used herein, the term “halo” or “halogen” refers to any radical offluorine, chlorine, bromine or iodine.

The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms. The expression “lower alkyl” refers to alkyl groups of 1 to 4carbon atoms (inclusive).

The term “arylalkyl” refers to a moiety in which an alkyl hydrogen atomis replaced by an aryl group.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups of 2 to 10, preferably 2 to 4, carbon atoms having at least onedouble bond. Where an alkenyl group is bonded to a nitrogen atom, it ispreferred that such group not be bonded directly through a carbonbearing a double bond.

The term “alkoxy” refers to an —O-alkyl radical. The term“alkylenedioxo” refers to a divalent species of the structure —O—R—O—,in which R represents an alkylene.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups of 2 to 10, preferably 2 to 4, carbon atoms having at least onetriple bond. Where an alkynyl group is bonded to a nitrogen atom, it ispreferred that such group not be bonded directly through a carbonbearing a triple bond.

The term “alkylene” refers to a divalent straight chain bridge of 1 to 5carbon atoms connected by single bonds (e.g., —(CH₂)_(x)—, wherein x is1 to 5), which may be substituted with 1 to 3 lower alkyl groups.

The term “alkenylene” refers to a straight chain bridge of 2 to 5 carbonatoms having one or two double bonds that is connected by single bondsand may be substituted with 1 to 3 lower alkyl groups. Exemplaryalkenylene groups are —CH═CH—CH═CH—, —CH₂—CH═CH—, —CH₂—CH═CH—CH₂—,—C(CH₃)₂CH═CH— and —CH(C₂H₅)—CH═CH—.

The term “alkynylene” refers to a straight chain bridge of 2 to 5 carbonatoms that has a triple bond therein, is connected by single bonds, andmay be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylenegroups are —C≡C—, —CH₂—C≡C—, —CH(CH₃)C≡C— and —C≡C—CH(C₂H₅)CH₂—.

The terms “cycloalkyl” and “cycloalkenyl” as employed herein includessaturated and partially unsaturated cyclic, respectively, hydrocarbongroups having 3 to 12 carbons, preferably 3 to 8 carbons, and morepreferably 3 to 6 carbon.

The terms “Ar” or “aryl” refer to aromatic cyclic groups (for example 6membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ringsystems) which contain 6 to 14 carbon atoms. Exemplary aryl groupsinclude phenyl, naphthyl, biphenyl and anthracene.

“Heteroaryl” refers to a monocyclic or fused ring (i.e., rings whichshare an adjacent pair of atoms) group of 5 to 12 ring atoms containingone, two, three or four ring heteroatoms selected from N, O, or S, theremaining ring atoms being C, and, in addition, having a completelyconjugated pi-electron system, wherein 0, 1, 2, 3, or 4 atoms of eachring may be substituted by a substituent. Examples, without limitation,of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole,thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline,isoquinoline, purine and carbazole.

The terms “heterocycle”, “heterocyclic” or “heterocyclo” refer to fullysaturated or partially unsaturated cyclic groups, for example, 3 to 7membered monocyclic, 7 to 12 membered bicyclic, or 10 to 15 memberedtricyclic ring systems, which have at least one heteroatom in at leastone ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted bya substituent. Each ring of the heterocyclic group containing aheteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogenatoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfurheteroatoms may optionally be oxidized and the nitrogen heteroatoms mayoptionally be quaternized. The heterocyclic group may be attached at anyheteroatom or carbon atom of the ring or ring system.

The term “heterocyclyl” refers to fully saturated or partiallyunsaturated cyclic groups, for example, 3 to 7 membered monocyclic, 7 to12 membered bicyclic, or 10 to 15 membered tricyclic ring systems, whichhave at least one heteroatom in at least one ring, wherein 0, 1, 2 or 3atoms of each ring may be substituted by a substituent. Each ring of theheterocyclyl group containing a heteroatom may have 1, 2, 3 or 4heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfuratoms, where the nitrogen and sulfur heteroatoms may optionally beoxidized and the nitrogen heteroatoms may optionally be quaternized. Theheterocyclyl group may be attached at any heteroatom or carbon atom ofthe ring or ring system.

The term “substituents” refers to a group “substituted” on anyfunctional group delineated herein, e.g., alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl group at anyatom of that group. Suitable substituents include, without limitationhalogen, CN, NO₂, OR¹⁵, SR¹⁵, S(O)₂OR¹⁵, NR¹⁵R¹⁶, C₁-C₂ perfluoroalkyl,C₁-C₂ perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR¹⁵, C(O)NR¹⁵R¹⁶,OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶,S(O)₂NR¹⁵R¹⁶, R¹⁷, C(O)R¹⁷, NR¹⁵C(O)R¹⁷, S(O)R¹⁷, S(O)₂R¹⁷, R¹⁶, oxo,C(O)R¹⁶, C(O)(CH₂)nOH, (CH₂)nOR¹⁵, (CH₂)nC(O)NR¹⁵R¹⁶, NR¹⁵S(O)₂R¹⁷,where n is independently 0-6 inclusive. Each R¹⁵ is independentlyhydrogen, C₁-C₄ alkyl or C₃-C₆ cycloalkyl. Each R¹⁶ is independentlyhydrogen, alkenyl, alkynyl, C₃-C₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substituted with C₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R¹⁷ is independentlyC₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl or C₁-C₄alkyl substituted with C₃-C₆ cycloalkyl, aryl, heterocyclyl orheteroaryl. Each C₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl andC₁-C₄ alkyl in each R⁵, R¹⁶ and R¹⁷ can optionally be substituted withhalogen, CN, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, NH₂, C₁-C₄ alkylamino, C₁-C₄dialkylamino, C₁-C₂ perfluoroalkyl, C₁-C₂ perfluoroalkoxy, or1,2-methylenedioxy.

The term “oxo” refers to an oxygen atom, which forms a carbonyl whenattached to carbon, an N-oxide when attached to nitrogen, and asulfoxide or sulfone when attached to sulfur.

The term “acyl” refers to an alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent,any of which may be further substituted by substituents.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Therecitation of an embodiment herein includes that embodiment as anysingle embodiment or in combination with any other embodiments orportions thereof.

The compounds of this invention may contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures, singleenantiomers, individual diastereomers and diastereomeric mixtures. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. The compounds of this invention may also berepresented in multiple tautomeric forms, in such instances, theinvention expressly includes all tautomeric forms of the compoundsdescribed herein. All such isomeric forms of such compounds areexpressly included in the present invention. All crystal forms of thecompounds described herein are expressly included in the presentinvention.

Compounds of the Invention

In one aspect, the present invention provides a compound of Formula I:

or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or ahydrate, solvate, or polymorph thereof; wherein:

R₁, R₂, R₃, and R₄ each are independently H, alkyl, or Z¹;

R₆ is an unsaturated heterocyclyl, wherein R₆ is optionally substitutedby 1-3 groups, independently selected from alkyl, cycloalkyl,heterocyclyl, alkoxy, hydroxyalkyl, and Z¹;

Each Z¹ is halogen, CN, NO₂, OR¹⁵, SR¹⁵, S(O)₂OR¹⁵, NR¹⁵R¹⁶, C₁-C₂perfluoroalkyl, C₁-C₂ perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR¹⁵,C(O)NR¹⁵R¹⁶OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶,NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶, R¹⁷, C(O)R¹⁷, NR¹⁵C(O)R¹⁷, S(O)R¹⁷,S(O)₂R¹⁷, R¹⁶, oxo, C(O)R¹⁶, C(O)(CH₂)nOH, (CH₂)nOR¹⁵,(CH₂)nC(O)NR¹⁵R¹⁶, NR¹⁵S(O)₂R¹⁷, where each n is independently 0-6;

Each R¹⁵ is independently hydrogen, C₁-C₄ alkyl or C₃-C₆ cycloalkyl;

Each R¹⁶ is independently hydrogen, alkenyl, alkynyl, C₃-C₆ cycloalkyl,aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substitutedwith C₃-C₆ cycloalkyl, aryl, heterocyclyl or heteroaryl; and

Each R¹⁷ is independently C₃-C₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substituted with C₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl.

In one embodiment, the invention provides for a compound of formula II:

or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or ahydrate, solvate, or polymorph thereof; wherein R₁, R₂, R₃, R₄, R₇ andR₈ each are independently H, alkyl or Z¹;

Each Z¹ is halogen, CN, NO₂, OR¹⁵, SR¹⁵, S(O)₂OR⁵, NR¹⁵R¹⁶, C₁-C₂perfluoroalkyl, C₁-C₂ perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR¹⁵,C(O)NR¹⁵R¹⁶OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶,NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶, R¹⁷, C(O)R¹⁷, NR¹⁵C(O)R¹⁷, S(O)R¹⁷,S(O)₂R¹⁷, R¹⁶, oxo, C(O)R¹⁶, C(O)(CH₂)nOH, (CH₂)nOR¹⁵,(CH₂)nC(O)NR¹⁵R¹⁶, NR¹⁵S(O)₂R¹⁷, where each n is independently 0-6;

Each R¹⁵ is independently hydrogen, C₁-C₄ alkyl or C₃-C₆ cycloalkyl;

Each R¹⁶ is independently hydrogen, alkenyl, alkynyl, C₃-C₆ cycloalkyl,aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substitutedwith C₃-C₆ cycloalkyl, aryl, heterocyclyl or heteroaryl; and

Each R¹⁷ is independently C₃-C₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substituted with C₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl.

In another embodiment, the invention provides for a compound of formulaIII:

or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or ahydrate, solvate, or polymorph thereof; wherein R₇ and R₈ each areindependently H, alkyl or Z¹;

Each Z¹ is halogen, CN, NO₂, OR¹⁵, SR¹⁵, S(O)₂OR⁵, NR¹⁵R¹⁶, C₁-C₂perfluoroalkyl, C₁-C₂ perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR⁵,C(O)NR¹⁵R¹⁶ OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶,NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶, R¹⁷, C(O)R¹⁷, NR¹⁵C(O)R¹⁷, S(O)R¹⁷,S(O)₂R¹⁷, R¹⁶, oxo, C(O)R¹⁶, C(O)(CH₂)nOH, (CH₂)nOR¹⁵,(CH₂)nC(O)NR¹⁵R¹⁶, NR¹⁵S(O)₂R¹⁷, where each n is independently 0-6;

Each R¹⁵ is independently hydrogen, C₁-C₄ alkyl or C₃-C₆ cycloalkyl;

Each R¹⁶ is independently hydrogen, alkenyl, alkynyl, C₃-C₆ cycloalkyl,aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substitutedwith C₃-C₆ cycloalkyl, aryl, heterocyclyl or heteroaryl; and

Each R¹⁷ is independently C₃-C₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substituted with C₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl.

Representative compounds of the invention are depicted in Table 1. Inthese examples the stereochemistry at the chiral carbon atoms isindependently either RS, R, or S, unless specified. The structuresdepicted herein, including the Table 1 structures, may contain certain—NH—, —NH₂ (amino) and —OH (hydroxyl) groups where the correspondinghydrogen atom(s) do not explicitly appear; however they are to be readas —NH—, —NH₂ or —OH as the case may be. In certain structures, a stickbond is drawn and is meant to depict a methyl group.

TABLE 1

1

2

3

5

6

7

Representative compounds of the invention are listed below:

-   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;-   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;-   {5-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;-   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;-   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[1-(2-methoxyethyl)-6-oxo-1,6-dihydro-pyridin-3-yl]carboxamide;-   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-ethyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide.

The synthesis of compounds of the formulae herein can be readilyeffected by synthetic chemists of ordinary skill. Relevant proceduresand intermediates are disclosed, for instance, herein. Each of thepatents, patent applications, and publications, whether in traditionaljournals or available only through the internet, referred to herein, isincorporated in its entirety by reference.

Other approaches to synthesizing compounds of the formulae herein canreadily be adapted from references cited herein. Variations of theseprocedures and their optimization are within the skill of the ordinarypractitioner.

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (e.g., R¹,R², R, R′, X, etc.) or not. The suitability of a chemical group in acompound structure for use in synthesis of another compound structure iswithin the knowledge of one of ordinary skill in the art. Additionalmethods of synthesizing compounds of the formulae herein and theirsynthetic precursors, including those within routes not explicitly shownin schemes herein, are within the means of chemists of ordinary skill inthe art. Methods for optimizing reaction conditions, if necessaryminimizing competing by-products, are known in the art. The methodsdescribed herein may also additionally include steps, either before orafter the steps described specifically herein, to add or remove suitableprotecting groups in order to ultimately allow synthesis of thecompounds herein. In addition, various synthetic steps may be performedin an alternate sequence or order to give the desired compounds.Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the applicablecompounds are known in the art and include, for example, those describedin R. Larock, Comprehensive Organic Transformations, VCH Publishers(1989); T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley and Sons (1999); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wileyand Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995) and subsequent editionsthereof.

The methods delineated herein contemplate converting compounds of oneformula to compounds of another formula. The process of convertingrefers to one or more chemical transformations, which can be performedin situ, or with isolation of intermediate compounds. Thetransformations can include reacting the starting compounds orintermediates with additional reagents using techniques and protocolsknown in the art, including those in the references cited herein.Intermediates can be used with or without purification (e.g.,filtration, distillation, sublimation, crystallization, trituration,solid phase extraction, and chromatography).

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

The invention also provides compositions comprising an effective amountof a compound of any of the formulae herein, or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph or prodrug, if applicable,of said compound; and an acceptable carrier. Preferably, a compositionof this invention is formulated for pharmaceutical use (“apharmaceutical composition”), wherein the carrier is a pharmaceuticallyacceptable carrier. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and, inthe case of a pharmaceutically acceptable carrier, not deleterious tothe recipient thereof in amounts typically used in medicaments.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch). Other formulations may conveniently bepresented in unit dosage form, e.g., tablets and sustained releasecapsules, and in liposomes, and may be prepared by any methods wellknown in the art of pharmacy. See, for example, Remington'sPharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa.(17th ed. 1985).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers or both, and then if necessary shaping theproduct.

In certain preferred embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion, or packed in liposomes and as a bolus,etc. Soft gelatin capsules can be useful for containing suchsuspensions, which may beneficially increase the rate of compoundabsorption.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface-active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets optionally may be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. Methods of formulating such slow or controlledrelease compositions of pharmaceutically active ingredients, such asthose herein and other compounds known in the art, are known in the artand described in several issued US patents, some of which include, butare not limited to, U.S. Pat. Nos. 4,369,172; and 4,842,866, andreferences cited therein. Coatings can be used for delivery of compoundsto the intestine (see, e.g., U.S. Pat. Nos. 6,638,534, 5,217,720, and6,569,457, 6,461,631, 6,528,080, 6,800,663, and references citedtherein). A useful formulation for the compounds of this invention isthe form of enteric pellets of which the enteric layer compriseshydroxypropylmethylcellulose acetate succinate.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for topical administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Particularly favored derivatives and prodrugs are those that increasethe bioavailability of the compounds of this invention when suchcompounds are administered to a mammal (e.g., by allowing an orallyadministered compound to be more readily absorbed into the blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or central nervous system) relative to theparent species. Preferred prodrugs include derivatives where a groupthat enhances aqueous solubility or active transport through the gutmembrane is appended to the structure of formulae described herein. See,e.g., Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31,318-322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp1-92; Bundgaard, H.; Nielsen, N. M. Journal of Medicinal Chemistry 1987,30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development;Harwood Academic Publ.: Switzerland, 1991; pp 113-191; Digenis, G. A. etal. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, G.J.; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.;Overseas Publ.: Amsterdam, 1996; pp 351-385; Pitman, I. H. MedicinalResearch Reviews 1981, 1, 189-214.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

In another embodiment, a composition of the present invention furthercomprises a second therapeutic agent. The second therapeutic agentincludes any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered alone or with acompound of any of the formulae herein. Drugs that could be usefullycombined with these compounds include other kinase inhibitors and/orother chemotherapeutic agents for the treatment of the diseases anddisorders discussed above.

Such agents are described in detail in the art. Preferably, the secondtherapeutic agent is an agent useful in the treatment or prevention of adisease or condition selected from cancer.

Even more preferably the second therapeutic agent co-formulated with acompound of this invention is an agent useful in the treatment of c-met,ron, or ALK and its fusion proteins such as EML4-ALK and NPM-ALKmediated disease/disorders. Even more preferably the second therapeuticagent co-formulated with a compound of this invention is an agent usefulin the treatment of c-met mediated disorder.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and a second therapeutic agent that areassociated with one another. The term “associated with one another” asused herein means that the separate dosage forms are packaged togetheror otherwise attached to one another such that it is readily apparentthat the separate dosage forms are intended to be sold and administeredtogether (within less than 24 hours of one another, consecutively orsimultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to reduce or ameliorate theseverity, duration or progression of the disorder being treated, preventthe advancement of the disorder being treated, cause the regression ofthe disorder being treated, or enhance or improve the prophylactic ortherapeutic effect(s) of another therapy.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother Rep 50: 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537.An effective amount of a compound of this invention can range from about0.001 mg/kg to about 500 mg/kg, more preferably 0.01 mg/kg to about 50mg/kg, more preferably 0.1 mg/kg to about 2.5 mg/kg. Effective doseswill also vary, as recognized by those skilled in the art, depending onthe diseases treated, the severity of the disease, the route ofadministration, the sex, age and general health condition of thepatient, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare entirely incorporated herein by reference.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, its will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

According to another embodiment, the invention provides a method oftreating a subject suffering from or susceptible to a disease ordisorder or symptom thereof (e.g., those delineated herein) comprisingthe step of administering to said subject an effective amount of acompound or a composition of this invention. Such diseases are wellknown in the art and are also disclosed herein.

In one aspect, the method of treating involves treatment of a disorderthat is mediated by the protein kinase, e.g. c-met, ron.

In another aspect, the invention provides a method of treating a diseasein a subject comprising administering to the subject a compound of anyof the formulae herein.

In another aspect, invention provides a method of treating a disease ina subject comprising administering to the subject a compositioncomprising a compound of any of the formulae herein.

In certain embodiments, the disease is mediated by the c-met or ronkinases.

In another embodiment, the disease is cancer or a proliferation disease.

In yet another embodiment, the disease is cancer of the lung, colon,breast, prostate, liver, pancreas, brain, kidney, ovaries, stomach, orskin, or bone cancers, gastric cancer, breast cancer, pancreatic cancer,glioma, and hepatocellular carcinoma, papillary renal carcinoma, or headand neck squamous cell carcinoma.

In a one embodiment, the method of this invention is used to treat asubject suffering from or susceptible to a disease or condition. Suchdiseases, disorders or symptoms thereof include, for example, thosemodulated by a protein kinase (e.g., c-met, ron). The disease or diseasesymptom can be, for example, cancer or proliferation disease ordisorder. The disease or disease symptom can be lung, colon, breast,prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin, andbone cancers, gastric cancer, breast cancer, pancreatic cancer, glioma,and hepatocellular carcinoma, papillary renal carcinoma, or head andneck squamous cell carcinoma. Methods delineated herein include thosewherein the subject is identified as in need of a particular statedtreatment. Identifying a subject in need of such treatment can be in thejudgment of a subject or a health care professional and can besubjective (e.g. opinion) or objective (e.g. measurable by a test ordiagnostic method).

In another embodiment, the invention provides a method of modulating theactivity of a protein kinase (e.g. protein tyrosine kinase, kinaseslisted herein) in a cell comprising contacting a cell with one or morecompounds of any of the formulae herein.

In another embodiment, the above method of treatment comprises thefurther step of co-administering to said patient one or more secondtherapeutic agents. The choice of second therapeutic agent may be madefrom any second therapeutic agent known to be useful for indicationsherein. Additional therapeutic agents include but are not limited toagents for treatment of diseases, disorders or symptoms thereofincluding for example, anticancer agents, antiproliferative agents,antineoplastic agents, antitumor agents, antimetabolite-type/thymidilatesynthase inhibitor antineoplastic agents, alkylating-type antineoplasticagents, antibiotic-type antineoplastic agents, or, any other agenttypically administered as a primary or adjuvant agent in cancertreatment protocols (e.g., antinausea, antianemia, etc.), including forexample, vinblastine sulfate, vincristine, vindesine, vinestramide,vinorelbine, vintriptol, vinzolidine, tamoxifen, toremifen, raloxifene,droloxifene, iodoxyfene, megestrol acetate, anastrozole, letrazole,borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproteroneacetate, goserelin acetate, luprolide, finasteride, herceptin,methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin,mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulphan,cyclophosphamide, ifosfamide, nitrosoureas, thiotephan, vincristine,taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan,topotecan, an epothilone, Iressa, Avastin, OSI-774, angiogenesisinhibitors, EGFR inhibitors, MEK inhibitors, VEGFR inhibitors, CDKinhibitors, Her1 and Her2 inhibitors and monoclonal antibodies.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention comprising both a compound of theinvention and a second therapeutic agent to a subject does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidsubject at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofany of the formulae herein alone or together with one or more of theabove-described second therapeutic agents in the manufacture of amedicament, either as a single composition or as separate dosage forms,for treatment or prevention in a subject of a disease, disorder orsymptom set forth above. Another aspect of the invention is a compoundof the formulae herein for use in the treatment or prevention in asubject of a disease, disorder or symptom thereof delineated herein.

In other aspects, the methods herein include those further comprisingmonitoring subject response to the treatment administrations. Suchmonitoring may include periodic sampling of subject tissue, fluids,specimens, cells, proteins, chemical markers, genetic materials, etc. asmarkers or indicators of the treatment regimen. In other methods, thesubject is prescreened or identified as in need of such treatment byassessment for a relevant marker or indicator of suitability for suchtreatment.

In one embodiment, the invention provides a method of monitoringtreatment progress. The method includes the step of determining a levelof diagnostic marker (Marker) (e.g., any target or cell type delineatedherein modulated by a compound herein) or diagnostic measurement (e.g.,screen, assay) in a subject suffering from or susceptible to a disorderor symptoms thereof delineated herein, in which the subject has beenadministered a therapeutic amount of a compound herein sufficient totreat the disease or symptoms thereof. The level of Marker determined inthe method can be compared to known levels of Marker in either healthynormal controls or in other afflicted patients to establish thesubject's disease status. In preferred embodiments, a second level ofMarker in the subject is determined at a time point later than thedetermination of the first level, and the two levels are compared tomonitor the course of disease or the efficacy of the therapy. In certainpreferred embodiments, a pre-treatment level of Marker in the subject isdetermined prior to beginning treatment according to this invention;this pre-treatment level of Marker can then be compared to the level ofMarker in the subject after the treatment commences, to determine theefficacy of the treatment.

In certain method embodiments, a level of Marker or Marker activity in asubject is determined at least once. Comparison of Marker levels, e.g.,to another measurement of Marker level obtained previously orsubsequently from the same patient, another patient, or a normalsubject, may be useful in determining whether therapy according to theinvention is having the desired effect, and thereby permittingadjustment of dosage levels as appropriate. Determination of Markerlevels may be performed using any suitable sampling/expression assaymethod known in the art or described herein. Preferably, a tissue orfluid sample is first removed from a subject. Examples of suitablesamples include blood, urine, tissue, mouth or cheek cells, and hairsamples containing roots. Other suitable samples would be known to theperson skilled in the art. Determination of protein levels and/or mRNAlevels (e.g., Marker levels) in the sample can be performed using anysuitable technique known in the art, including, but not limited to,enzyme immunoassay, ELISA, radiolabelling/assay techniques,blotting/chemiluminescence methods, real-time PCR, and the like.

The present invention also provides kits for use to treat diseases,disorders, or symptoms thereof, including those delineated herein. Thesekits comprise: a) a pharmaceutical composition comprising a compound ofany of the formula herein or a salt thereof; or a prodrug, or a salt ofa prodrug thereof; or a hydrate, solvate, or polymorph thereof, whereinsaid pharmaceutical composition is in a container; and b) instructionsdescribing a method of using the pharmaceutical composition to treat thedisease, disorder, or symptoms thereof, including those delineatedherein.

The container may be any vessel or other sealed or sealable apparatusthat can hold said pharmaceutical composition. Examples include bottles,divided or multi-chambered holders bottles, wherein each division orchamber comprises a single dose of said composition, a divided foilpacket wherein each division comprises a single dose of saidcomposition, or a dispenser that dispenses single doses of saidcomposition. The container can be in any conventional shape or form asknown in the art which is made of a pharmaceutically acceptablematerial, for example a paper or cardboard box, a glass or plasticbottle or jar, a re-sealable bag (for example, to hold a “refill” oftablets for placement into a different container), or a blister packwith individual doses for pressing out of the pack according to atherapeutic schedule. The container employed can depend on the exactdosage form involved, for example a conventional cardboard box would notgenerally be used to hold a liquid suspension. It is feasible that morethan one container can be used together in a single package to market asingle dosage form. For example, tablets may be contained in a bottle,which is in turn contained within a box. Preferably, the container is ablister pack.

The kit may additionally comprising information and/or instructions forthe physician, pharmacist or subject. Such memory aids include numbersprinted on each chamber or division containing a dosage that correspondswith the days of the regimen which the tablets or capsules so specifiedshould be ingested, or days of the week printed on each chamber ordivision, or a card which contains the same type of information.

The compounds delineated herein can be assessed for their biologicalactivity using protocols known in the art, including for example, thosedelineated herein. Certain of the compounds herein demonstrateunexpectedly superior attributes (e.g., inhibition of P450, Met, Ron,etc.; pharmacokinetic properties, etc.) making them superior candidatesas potential therapeutic agents.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, technical datasheets, internet web sites, databases, patents, patent applications, andpatent publications.

EXAMPLES Synthesis of5-[(2,6-dichloro-3-fluorophenyl)ethoxy]-6-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}pyridazine-3-carboxylicacid (A)

Step 1: A suspension of A1 (400 g, 2.68 mol) in 25% ammonium hydroxide(3 L) was heated at 130° C. for 12 h in a sealed stainless autoclave.After the tube was cooled to 0° C., the mixture was filtered. Theresulting solid was washed with water for several times and dried undervacuo to provide A2 (284 g, 82%).

Step 2: To a solution of A2 (284 g, 2.19 mol) in methanol (3.5 L) wasadded NaHCO₃ (368.4 g, 4.38 mol) at room temperature, followed bybromine (350 g, 2.19 mol) drop-wise. After the addition was complete,the mixture was stirred for 20 h, then filtered and washed by methanolfor several times. The filtrate was concentrated and the residue wasdissolved in water (2 L) and extracted with ethyl acetate (2 L×3). Thecombined organic phase was washed with 10% sodium thiosulfate aq. (2 L),sat. sodium bicarbonate aq. (2 L) and brine (2 L), dried over anhydrousmagnesium sulfate and evaporated. The residue was purified by columnchromatography (EA:PE=2:1) to provide A3 (159.8 g, 35%).

Step 3: To a solution of A4 (150 g, 0.72 mol) in methanol (800 mL)cooled to 0° C., was added NaBH₄ (66 g, 1.74 mol) in portions. Theresulting mixture was stirred at r.t. for about 1 h and evaporated.Water (1 L) was added to the residue at 0° C., followed by 3N HCl untilpH=6. The resulting mixture was extracted with ethyl acetate (400 mL×4).The combined organic phase was dried over anhydrous sodium sulfate,filtered and concentrated to give A5 (148.6 g, 98%).

Step 4: To a solution of A5 (147.6 g, 0.71 mol) in THF (3 L) was added60% NaH (28.4 g, 0.71 mol) at 0° C., the resulting mixture was stirredat that temperature for 30 min, was then added A3 (147 g, 0.71 mmol)quickly. The resulting mixture was heated under reflux overnight andevaporated. The residue was purified by column chromatography(PE:EA=4:1) to provide the advanced intermediate A6 (89.3 g, 37.6%).

Step 5: To a solution of A6 (97 g, 0.288 mol) in DMF (1 L) was addedBoc₂O (113 g, 0.519 mol) and DMAP (7 g, 58 mmol). The mixture wasstirred at r.t. overnight and evaporated. The residue was purified bycolumn chromatography (PE:EA=10:1) to afford A7 (136 g, 88%).

Step 6: Sodium acetate (41 g, 0.50 mol) was added to a solution of A7(136 g, 0.25 mol) in ethanol/DMF [(5:1) (1200 mL)]. The mixture wasdegassed, then added Pd(dppf)Cl₂.CH₂Cl₂ (18.63 g, 22.5 mmol). Theresulting mixture was heated at CO atmosphere at 90° C. for 1.5 h, thenevaporated. The residue was purified by column chromatography(PE:EA=1:4) to afford A8 (141 g, 97%).

Step 7: To the solution of A8 (141 g, 0.246 mol) in THF (650 mL) wasadded 1N LiOH aq. (390 mL). The resulting mixture was stirred at r.t.over weekend, then acidified by 2N HCl to pH=5, extracted with ethylacetate (300 mL×5). The combined organic phase was dried over Na₂SO₄,filtrated and concentrated to give A (134 g, 99%).

Synthesis of6-[bis(tert-butoxycarbonyl)amino]-5-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridazine-3-carboxylicacid (B)

Step 1: To a solution of A5 (219 g, 1.05 mol) in 1,2-dichloroethane(3500 mL) was added Boc-D-Pro (141 g, 0.65 mol) followed by EDCI (163 g,0.85 mol) and DMAP (21.57 g, 0.18 mol) at 0° C. The resulting mixturewas stirred at r.t. overnight and then water (3500 mL) was added andseparated, the water phase was extracted with DCM (1500 mL×3), driedover MgSO₄, concentrated and purified by column chromatography to(PE:EA=30:1) to give B1 (55.96 g, yield: 51.1%)

Step 2: To a solution of B1 (59.96 g, 268 mmol) in THF (1200 mL) wasadded 60% NaH (10.71 g, 268 mmol) at 0° C., the resulting mixture wasstirred at that temperature for 30 min, was then added A3 (55.82 g, 268mmol) quickly. The resulting mixture was heated under reflux overnightand evaporated. The residue was purified by column chromatography(PE:EA=4:1) to provide the advanced intermediate B2 (33.95 g, 37.7%).1H-NMR (300 MHz, CDCl₃): δ=1.87 (d, 3H), 5.08 (s, 2H), 6.03-6.09 (m,1H), 6.42 (s, 1H), 7.14 (t, 1H), 7.35 (dd, 1H). LC-MS [M+H]⁺: 336.0.

Step 3: To a solution of B2 (33.95 g, 101 mmol) in DMF (400 mL) wasadded BOC₂O (39.59 g, 182 mmol) and DMAP (2.46 g, 20.2 mmol). Themixture was stirred at r.t. overnight and evaporated. The residue waspurified by column chromatography (PE:EA=10:1) and the residue wastreated with PE:EA=10:1 to afford B3 (46.9 g, 86.7%).

Step 4: Sodium acetate (14.34 g, 175 mmol) was added to a solution of B3(46.9 g, 87.4 mmol) in ethanol/DMF [(5:1) (480 mL)]. The mixture wasdegassed, then added Pd(dppf)Cl₂.CH₂Cl₂ (7.14 g, 8.74 mmol). Theresulting mixture was heated at CO atmosphere at 90° C. overnight, thenevaporated. The residue was purified by column chromatography(PE:EA=4:1) to afford B4 (47.1 g, 94.0%). 1H-NMR (300 MHz, CDCl₃):δ=1.38 (s, 18H), 1.46 (t, 3H), 1.88 (d, 3H), 4.45-4.53 (m, 2H), 6.18 (q,1H), 7.13 (t, 1H), 7.34 (dd, 1H), 7.57 (s, 1H). LC-MS [M+H]⁺: 574.0.

Step 5: To the solution of B4 (47.1 g, 82.1 mmol) in THF (400 mL) wasadded 1N LiOH aq. (98.5 mL). The resulting mixture was stirred at r.t.over weekend, then acidified by 2N HCl to pH=5, extracted with ethylacetate (400 mL×3). The combined organic phase was dried over Na₂SO₄,filtrated and concentrated to give B (45.94 g, ˜100%).

Synthesis of6-[bis(tert-butoxycarbonyl)amino]-5-[(1S)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridazine-3-carboxylicacid (C)

Step 1: To a solution of A5 (41.8 g, 200 mmol) in 1,2-dichloroethane(800 mL) was added Boc-L-Pro (26.9 g, 125 mmol) followed by EDCI (31.1g, 163 mmol) and DMAP (4.12 g, 33.8 mmol) at 0° C. The resulting mixturewas stirred at r.t. overnight and then water (350 mL) was added andseparated, the water phase was extracted with DCM (150 mL×3), dried overMgSO₄, concentrated and purified by column chromatography to(PE:EA=30:1) to give C1 (13.72 g, yield: 65.6%).

Step 2: The procedure from C1 to C was similar to that of B1 to B (9.46g, yield: 26.4% from C1).

Example 1 Synthesis of{5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide

Step 1: To a solution of 1a (16.0 g, 114 mmol) in DMF (500 mL) was addedNaH (5.5 g, 137 mmol). The suspension was stirred at 0° C. for 0.5 h andadded CH₃I (17.8 g, 126 mmol) dropwise at 0° C. The resulting mixturewas allowed to warm to r.t. for 1 h and evaporated. The residue wasadded sat. NaHCO₃ (50 mL) and water (50 mL). The suspension wasextracted with DCM (300 mL) twice. The combined extract was washedwater, dried over MgSO₄ and concentrated. The residue was retreated withPE:EA=10:1 to provide 1b (11.05 g, 63.0%).

Step 2: Reductive iron powder (39.0 g, 69.6 mmol) and 2N HCl (20 mL)were added to a stirred solution of 1b (15.4 g, 100 mmol) in ethanol(300 mL) at 0° C. The resulting mixture was heated under reflux for 2 hand filtrated. The brown solid was washed with ethanol for severaltimes. The combined ethanol phase was evaporated and the residue wasdissolved in ethyl acetate (400 mL) and washed with 1.5N Na₂CO₃ aq. (400mL). The bi-phase mixture was separated and the water phase wasre-extracted with ethyl acetate (250 mL×3). The combined organic phasewas dried over MgSO₄, filtered and evaporated to give 1c (10.0 g,80.6%).

Step 11: The mixture of B (20.00 g, 36.6 mmol), HATU (28.00 g, 73.7mmol) and DIEA (14 g, 108.5 mmol) in DMF (200 mL) was stirred at roomtemperature for 0.5 h, then was added 1c (10 g, 81.9 mmol). Theresulting mixture was stirred at room temperature for 0.5 h andevaporated. The residue was purified by column chromatography(EA:MeOH=5:1) to provide 1d (18.0 g, 75.4%).

Step 12: 1d (18.0 g, 27.6 mmol) was dissolved in a mixture of DCM (150mL) and TFA (50 mL), stirred at r.t. for 2 hours and evaporated. Theresidue was adjusted by sat. Na₂CO₃ to pH=8 and extracted with DCM (200mL×5). The combined organic phase was dried over MgSO₄ and concentrated.The residue was triturated with methanol and filtered, then the solidwas dissolved in DCM and a solution of HCl in Et₂O was added, themixture was stirred at r.t. overnight, then concentrated and dried overoil pump to afford 1 (13.5 g, 84.1% from 1d). 1H-NMR (300 MHz, DMSO-d₆):δ=1.82 (d, 3H), 3.41 (s, 3H), 6.24 (q, 1H), 6.38 (d, 1H), 7.04 (s, 1H),7.42-7.66 (m, 3H), 8.17 (s, 1H). LC-MS [M+H]⁺: 452.0.

Example 2 Synthesis of{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide

The procedure from A to 2 was similar to that in Example 1 (70 mg, 42%from A). 1H-NMR (300 MHz, CDCl₃): δ=1.89 (d, 3H), 3.57 (s, 3H), 5.40 (s,2H), 6.21-6.27 (m, 1H), 6.59 (d, 1H), 7.06-7.12 (m, 1H), 7.26-7.37 (m,3H), 8.28 (d, 1H), 9.40 (s, 1H). LC-MS [M+H]⁺: 451.9.

Example 3 Synthesis of{5-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide

The procedure from C to 3 was similar to that in Example 1 to give 3(1.29 g, yield: 71.3% from 7c). 1H-NMR (300 MHz, DMSO-d6): δ=1.86 (d,3H), 3.42 (s, 3H), 6.27 (q, 1H), 6.41 (d, 1H), 7.06 (s, 1H), 7.52 (t,1H), 7.61-7.70 (m, 2H), 8.23 (d, 1H), 10.47 (s, 1H). LC-MS [M+H]⁺:452.1.

Example 4 Synthesis of{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-methyl-6-oxo(3-piperidyl)carboxamide

Step 1: To a solution of 1b in methanol was added 10% Pd/C. The mixturewas hydrogenated under H2 atmosphere overnight. Pd/C was filtered offand the filtrate was evaporated to provide crude 4a which was used fornext step without purification.

Step 2: The procedure from 4a to 4 was similar to that in Example 1 (131mg, 21% from A). 1H-NMR (300 MHz, CDCl₃): δ=1.88 (d, 3H), 1.92-2.08 (m,2H), 2.47-2.54 (m, 2H), 2.92 (d, 3H), 3.20-3.27 (m, 1H), 3.59-3.65 (m,1H), 4.39-4.42 (m, 1H), 5.37 (s, 2H), 6.18-6.24 (m, 1H), 7.06-7.11 (m,1H), 7.31-7.36 (m, 2H), 7.95 (d, 1H). LC-MS [M+H]⁺: 457.1.

Example 5 Synthesis of{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide

Step 1: The procedure from 1a to 5a was similar to that of 1b to 1cwhich provided 2a which was used for next step without purification.

Step 2: The procedure from 2a to 5 was similar to that in Example 1 (6.8mg, 4.2% from 5a). 1H-NMR (300 MHz, DMSO-d₆): δ=1.82 (d, 3H), 6.14-6.21(m, 1H), 6.32 (d, 1H), 6.89 (s, 2H), 6.99 (s, 1H), 7.47 (t, 1H),7.56-7.61 (m, 1H), 7.76-7.80 (m, 1H), 7.93 (s, 1H), 10.40 (s, 1H), 11.41(brs, 1H). LC-MS [M+H]⁺: 437.9.

Example 6 Synthesis of{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[1-(2-methoxyethyl)-6-oxo-1,6-dihydro-pyridin-3-yl]carboxamide

The synthesis was similar to that of Example 1 (157 mg, 56% from B).1H-NMR (300 MHz, CDCl₃): δ=1.89 (d, 3H), 3.32 (s, 3H), 3.69 (t, 2H),4.10-4.15 (m, 2H), 5.38 (s, 2H), 6.23-6.27 (m, 1H), 6.58 (d, 1H),7.07-7.12 (m, 1H), 7.32-7.44 (m, 3H), 8.13 (d, 1H), 9.39 (s, 1H). LC-MS[M+H]⁺: 496.0.

Example 7 Synthesis of{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-ethyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide

Step 1: Sodium hydride (0.63 g of a 60% dispersion in mineral oil, 15.8mmol) is added to a solution of compound 1a (2 g, 14.4 mmol) in DMF (20mL) at room temperature and stirred for 30 min. Ethyl iodide (2.2 g,14.4 mmol) is added to the reaction mixture and stirred for 16 hours atroom temperature. The reaction mixture is diluted with ethyl acetate,washed with water, dried over sodium sulfate and concentrated undervacuo to give compound 7a (2 g, 60%).

Step 2: A mixture of compound 7a (5 g, 29.7 mmol), Fe (6.7 g, 119 mmol)in AcOH (5 mL), water (50 mL) and MeOH (50 mL) was heated to reflux for30 min. The solvent was removed in vacuo and the residue was purified bycolumn chromatography to give compound 7b (2.5 g, 60%).

Step 3: To a solution of compound 7b (1 g, 7.25 mmol) in DMF (30 ml) wasadded HATU (4.13 g, 10.87 mmol) and compound B (20 mg, 163 mmol), DIEA(3.8 mL, 21.74 mmol), and the mixture was stirred at room temperatureovernight. The reaction mixture was treated with water and extractedwith EA. The organic layer was washed with brine, dried over MgSO₄ andconcentrated under reduce pressure, the crude product was purified byflash chromatography (DCM:MeOH=10:1) to afford compound 7c (3.2 g, 66%).

Step 4: To the solution of compound 7c (2 g, 3 mmol) in DCM (5 mL) wasadded TFA (3 mL). The mixture was stirred at room temperature for 4 hand evaporated. The residue was purified by column chromatography(DCM:MeOH=20:1) to provide 7 (700 mg, 50%). 1H-NMR (300 MHz, DMSO-d6):δ=10.04 (s, 1H), 8.23-8.24 (d, 1H), 7.69-7.73 (dd, 1H), 7.56-7.61 (m,1H), 7.44-7.50 (t, 1H), 6.97 (s, 1H), 6.92 (s, 2H), 6.33-6.37 (d, 1H),6.15-6.18 (q, 1H), 3.85-3.92 (q, 2H), 1.80-1.82 (d, 3H), 1.17-1.22 (t,3H), LC-MS [M+H]⁺: 467.0.

Example 8 Biological Data

Met, ALK Biochemical Assays

Kinase Assays. Assays were performed as described in Fabian et al.(2005) Nature Biotechnology, vol. 23, p. 329 and in Karaman et al.(2008) Nature Biotechnology, vol. 26, p. 127.

For most assays, kinase-tagged T7 phage strains were grown in parallelin 24-well blocks in an E. coli host derived from the BL21 strain. E.coli were grown to log-phase and infected with T7 phage from a frozenstock (multiplicity of infection ˜0.1) and incubated with shaking at 32°C. until lysis (˜90 minutes). The lysates were centrifuged (6,000×g) andfiltered (0.2 mm) to remove cell debris. The remaining kinases wereproduced in HEK-293 cells and subsequently tagged with DNA for qPCRdetection. Streptavidin-coated magnetic beads were treated withbiotinylated small molecule ligands for 30 minutes at room temperatureto generate affinity resins for kinase assays. The liganded beads wereblocked with excess biotin and washed with blocking buffer (SeaBlock(Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand andto reduce non-specific phage binding. Binding reactions were assembledby combining kinases, liganded affinity beads, and test compounds in 1×binding buffer (20% SeaBlock, 0.17×PBS, 0.05% Tween 20, 6 mM DTT). Testcompounds were prepared as 40× stocks in 100% DMSO and directly dilutedinto the assay. All reactions were performed in polypropylene 384-wellplates in a final volume of 0.04 ml. The assay plates were incubated atroom temperature with shaking for 1 hour and the affinity beads werewashed with wash buffer (1×PBS, 0.05% Tween 20). The beads were thenre-suspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 mMnon-biotinylated affinity ligand) and incubated at room temperature withshaking for 30 minutes. The kinase concentration in the eluates wasmeasured by qPCR.

Most examples in this invention with R₆ being unsaturated heterocycleare selective c-Met inhibitors. Specifically, the R-enantiomer (e.g.Example 1) or racemic mixture (e.g. Examples 2, 5, 6, and 7) providedIC₅₀ values of <5 nM in this c-Met assay, while the corresponding IC₅₀'sfor ALK were higher (>10 nM).

In contrast, the S-enantiomer (Example 3) did not show any significantinhibition at up to 50 nM in this c-Met assay.

Furthermore, the example with R₆ being a saturated heterocycle (Example4) had IC₅₀'s of >100 nM in both of the c-Met and ALK assays, while anexample (shown below) with R₆ being an aromatic ring was potent againstboth c-Met and ALK (IC₅₀<5 nM).

Therefore, the R-enantiomer of compound with R₆ being unsaturatedheterocycle (e.g. Example 1) has the surprising biological property ofbeing a potent and selective (compared to, at least, ALK) c-Metinhibitor.

c-Met Receptor Phosphorylation Assay

A549 cells are used in this assay. Cells are seeded at a density of40,000 cells/well in the growth media (RPMI+10% FBS) into 24-well platesand cultured overnight at 37° C. for attachment. Cells are exposed tothe starvation media (RPMI+1% BSA). Dilutions of the test compounds areadded to the plates and incubated at 37° C. for 1 hour. Cells are thencool down to room temperature for 15 min followed by stimulation with 40ng/ml HGF for 15 minutes. Cells are washed once with ice-cold PBS andthen lysed with 110 ul/well lysis buffer (Cell Signaling #9803+0.2%protease inhibitor, Sigma P1860) for 1 hour at 4° C. Cell lysates aretransferred to microcentrifuge tubes and are spun at 10000 rpm for 10min at 4° C. and phosphorylated HGFR is quantitated by Human Phospho-HGFR/c-Met ELISA kit (R&D, DYC2480) according to the manufacture'sinstructions.

In Vivo Anti-Tumor Efficacy of Compound 1 of EXAMPLE 1 Against U-87MGTumor Xenograft Model

(a) Selection of Cell Lines Based on Cellular Phosphorylation Status ofc-Met

HeLa, NIH-3T3, HEK293T, U87MG, PC3 and Caki were obtained from ATCC andwere cultured in 10 cm plates with full growth medium. Activelyproliferating cells were washed with 1×PBS once, and then lysed in thelysis buffer, pro-sonicated, and cleared by centrifugation for 10minutes at 10,000 rpm. Total protein was measured using a BCA proteinassay kit. Equal amounts of protein lysate for each cell line wereloaded for western blotting.

(b) Animal:

Balb/c nude mice (6 weeks old, male) were purchased from Shanghai SlacLaboratory Animal Co. Ltd (Shanghai, China). All mice were maintained ina pathogen-free facility for ˜2 weeks before implantation. They werehoused in plastic cages (4˜6 mice/cage) containing corn cob andmaintained in a pathogen-free facility (20˜25° C., 30˜70% humidity) witha 12-h light:dark cycle.

(c) Xenograft Human Tumor Model:

U-87 MG xenograft model was established by implanting athymic Balb/cnude mice s.c in the right flank with U-87 MG cells, 3.6×10⁶/mouse (120ul). Tumors were allowed to reach 120˜380 mm³ in size.

Group and Dosage:

Group n Dosage Treatment Vehicle Control 8 Formulation Vehicle ig, BID ×11 days EXAMPLE 1 8 25 mg/kg ig, BID × 11 days EXAMPLE 1 8 50 mg/kg ig,BID × 11 days Note: All treatments are given through oral gavage (10ml/kg). For multi-dosing a day, the second dose was given 7 hours afterthe first one.

(d) Observation Index

Tumor volumes were measured twice a week with caliper. Tumor volumeswere calculated by the formula <Tumor volume=length×width²/2>.

Percentage of tumor growth inhibition (GI) after initiation of treatmentwas calculated by the formula:GI=100×{1−[(tumor volume_(final)−tumor volume_(initial) for thecompound-treated group)/(tumor volume_(final)−tumor volume_(initial) forthe vehicle-treated group)]}Relative tumor volume is defined as the ratio of the volume at a giventime and the volume at the start of treatment. The relative tumor volume(RTV) was calculated by the formula:RTV=100×TV_(T)/TV₀

TV₀: tumor volume_(initial)

TV_(T): tumor volume at T time

The relative tumor growth rate (T/C %) was calculated by the formula:T/C %=100×T _(RTV) /C _(RTV)

T_(RTV): The relative tumor volume of treatment

C_(RTV): The relative tumor volume of control

Body weight of each mouse was weighed twice a week along with the tumorsize measurement. The Percentage of weight loss was calculated by theformula:Percentage of Weight Loss=100%×(Body Weight_(initial)−BodyWeight_(initial))/Body Weight_(initial)The tumor weight was measured by the end of experiment. The tumorinhibitory rate (IR) was calculated by the formula:IR=(W _(C) −W _(T))/W _(C)×100%.

(e) Results

The treatment started 24 days post tumour implantation while the averagetumor volume reached 230.52±8.04 mm³ (Mean±SE). After 11 days ofconsecutive treatment, EXAMPLE 1 at 25 and 50 mg/kg ig BID showedsignificant tumor growth inhibition (GI), with GI rates of 65.95%(P<0.01) and 88.71% (P<0.01) respectively. The results are summarized inTable 8.1 and FIG. 2.

TABLE 8.1 The effects of EXAMPLE 1 on the tumor volume (mean ± S.E inmm³) and GI (%) Days Post Implantation d24 d28 d31 d35 Vehicle 231.4 ±25.1 588.7 ± 53.0 971.9 ± 94.8 1483.0 ± 158.6 EXAMPLE 1, 230.4 ± 23.0365.7 ± 29.3** 453.7 ± 19.7**  627.7 ± 33.9** 25, BID GI 62.14% 77.04%65.95% EXAMPLE 1, 230.2 ± 24.5 305.9 ± 22.0** 337.4 ± 27.8**  371.5 ±34.4** 50, BID GI 78.82% 85.52% 88.71% Note: *donates P values <0.05,**donates P values <0.01 compared with vehicle control, respectively.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

What is claimed:
 1. A compound of formula I:

or a salt thereof; wherein: R₁, R₂, R₃, and R₄ each are independently H,alkyl, or Z¹; R₆ is an unsaturated heterocyclyl, wherein R₆ isoptionally substituted by 1- 3 groups independently selected from alkyl,cycloalkyl, heterocyclyl, alkoxy, hydroxyalkyl, and Z¹; Each Z¹ ishalogen, CN, NO₂, OR¹⁵, SR¹⁵, S(O)₂OR¹⁵, NR¹⁵R¹⁶, C₁-C₂ perfluoroalkyl,C₁-C₂ perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR¹⁵, C(O)NR¹⁵R¹⁶,OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶,NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶,S(O)₂NR¹⁵R¹⁶, R¹⁷,C(O)R¹⁷, NR¹⁵C(O)R¹⁷, S(O)R¹⁷,S(O)₂R¹⁷, R¹⁶, oxo, C(O)R¹⁶, C(O)(CH₂)_(n)OH, (CH₂)_(n) OR¹⁵,(CH₂)_(n)C(O)NR¹⁵R¹⁶,NR¹⁵S(O)₂R¹⁷, where each n is independently 0-6;Each R¹⁵ is independently hydrogen, C₁-C₄ alkyl or C₃-C₆ cycloalkyl;Each R¹⁶ is independently hydrogen, alkenyl, alkynyl,C₃-C₆ cycloalkyl,aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substitutedwith C₃-C₆ cycloalkyl, aryl, heterocyclyl or heteroaryl; and Each R¹⁷ isindependently C₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁-C₄alkyl or C₁-C₄ alkyl substituted with C₃-C₆ cycloalkyl, aryl,heterocyclyl or heteroaryl.
 2. A compound of formula II:

or a salt thereof; wherein R₁, R₂, R₃, R₄, R₇and R₅each areindependently H, alkyl or Z¹ ; Each Z¹is halogen, CN, NO₂, OR¹⁵, SR¹⁵,S(O)₂OR¹⁵, NR¹⁵R¹⁶, C₁-C₂perfluoroalkyl,C₁-C₂perfluoroalkoxy,1,2-methylenedioxy, C(O)OR¹⁵,C(O)NR¹⁵R¹⁶OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶,NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶, R¹⁷, C(O)R¹⁷, NR¹⁵C(O)R¹⁷, S(O)R¹⁷,S(O)₂R¹⁷, R¹⁶, oxo, C(O)R¹⁶,C(O)(CH₂)_(n)OH, (CH₂)_(n)OR¹⁵,(CH₂)_(n)C(O)NR¹⁵R¹⁶,NR¹⁵S(O)₂R¹⁷, where each n is independently 0-6;Each R¹⁵is independently hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl; EachR¹⁶is independently hydrogen, alkenyl, alkynyl, C₃-C₆cycloalkyl, aryl,heterocyclyl, heteroaryl, C₁-C₄alkyl or C₁-C₄alkyl substituted withC₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl; and Each R¹⁷isindependently C₃-C₆cycloalkyl, aryl, heterocyclyl, heteroaryl,C₁-C₄alkyl or C₁-C₄alkyl substituted with C₃-C₆cycloalkyl, aryl,heterocyclyl or heteroaryl.
 3. A compound of formula III:

or a salt thereof; wherein R₇and R₈each are independently H, alkyl orZ¹; Each Z¹is halogen, CN, NO₂, OR¹⁵ , SR¹⁵, S(O)₂OR¹⁵,NR¹⁵R¹⁶,C₁-C₂perfluoroalkyl, C₁-C₂perfluoroalkoxy,1,2-methylenedioxy,C(O)OR¹⁵, C(O)NR¹⁵R¹⁶, OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶,NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶, R¹⁷, C(O)R¹⁷, NR¹⁵C(O)R¹⁷, S(O)R¹⁷,S(O)₂R¹⁷, R¹⁶, oxo, C(O)R¹⁶, C(O)(CH₂)nOH,(CH₂)nOR¹⁵, (CH₂)nC(O)NR¹⁵R¹⁶,NR¹⁵S(O)₂R¹⁷, where each n is independently 0-6; Each R¹⁵isindependently hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl; Each R¹⁶isindependently hydrogen, alkenyl, alkynyl, C₃-C₆cycloalkyl, aryl,heterocyclyl, heteroaryl, C₁-C₄alkyl or C₁,-C₄alkyl substituted withC₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl; and Each R¹⁷isindependently C₃-C₆cycloalkyl, aryl, heterocyclyl, heteroaryl,C₁,-C₄alkyl or C₁, -C₄ alkyl substituted with C₃-C₆ cycloalkyl, aryl,heterocyclyl or heteroaryl.
 4. The compound of claim 3, wherein R₈ishydrogen and R₇is C₁-C₃alkyl.
 5. The compound of claim 3, wherein eachZ¹is independently halogen.
 6. The compound of claim 1, wherein thecompound is{5-[(1R)-1-(2,6-dichloro-3-fluoropheny)ethoxy]-6-aminopyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxarnide.7. The compound of claim 1, wherein the compound is selected from thefollowing:{6-amino-5[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;{5-[(1S)-1-(2,6dichloro-3-fluoropheny)ethoxy]-6-aminopyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[1-(2-methoxyethyl)-6oxo-1,6-dihydro-pyridin-3-yl]carboxamide;{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-ethyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide.